Tobacco use is a major health problem in the United States and schizophrenics smoke at a much higher rate that the general population (88-90% of schizophrenics versus 22% of the general population). The reason for this discrepancy is still unknown and many hypotheses have been introduced but none have been satisfactory in explaining the comorbidity. The reward circuitry has become a recent area of interest within schizophrenia research as anhedonia (inability to experience pleasure and/or reward) is considered a negative symptom of schizophrenia and antipsychotics have been shown to change how rewarding a stimulus is; however, there are only a limited number of studies on reward sensitivity in patients with schizophrenia and results so far have been mixed. This study purports to identify a novel hypothesis for the increase in nicotine use in schizophrenics that involves the reward system, i.e. a sensitivity to the reward- enhancement effects of nicotine. The reward-enhancement effect of nicotine is defined as enhancement by nicotine of non-nicotine stimuli and has proven to be a robust factor in the maintenance of nicotine use, producing an effect that may even be stronger than the general rewarding effect of nicotine. Sensitivity to the reward-enhancement effect of nicotine could provide an explanation for the high rate of smoking seen in patients with schizophrenia and lead to novel methods of treatment of this comorbidity. Using preclinical methods, this set of aims will provide three separate paradigms in which to test this idea: 50 kHz reward vocalizations, operant responding for a naturally rewarding stimulus (e.g. lights), and nicotine self- administration. Animals will be pretreated with either saline or phencyclidine (PCP), an NMDA receptor antagonist that has been validated as an animal model of schizophrenia and that produces many of the positive, negative, and cognitive symptoms that are shown in patients with the disorder. In the first two aims, vocalizations to a visual stimulus and lever-pressing for a visual stimulus will be measured after exposure to nicotine. In the third aim, lever-pressing for an injection of nicotine will be examined between groups that either receive nicotine alone or nicotine with a concurrent visual stimulus. This set of experiments will provide data not only on the potential sensitivity to the reward-enhancement effect of nicotine but also allow for analyses on the general rewarding effect of nicotine in a preclinical animal model of schizophrenia. PUBLIC HEALTH RELEVANCE: Nicotine addiction is a serious worldwide health issue but the rate of smoking in schizophrenic patients is vastly higher than the general population. A valid hypothesis that can explain why schizophrenics smoke could lead to disentangling the mechanisms behind this comorbidity as well as lead to research that could develop novel therapeutic treatments to lower the rate of smoking in this particular population.